Molecular transdermal transport system

ABSTRACT

An efficient transdermal delivery system for delivering an active ingredient to the blood supply of a living body, comprising a vasodilator, an active ingredient, a permeation enhancer for the active ingredient, and a water soluble gum for binding the foregoing. A non-breathable layer also can be used for controlling the microenvironment at the transport site. Compression can be used to further enhance the blood supply at the transport site.

This application is a continuation-in-part of U.S. Ser. No. 08/542,068filed Oct. 12, 1995 now U.S. Pat. No. 5,645,854, which is acontinuation-in-part of U.S. Ser. No. 08/227,365, filed Apr. 13, 1994,now U.S. Pat. No. 5,460,821, which is a continuation-in-part of U.S.Ser. No. 08/081,567 filed Jun. 23, 1993 (abandoned).

BACKGROUND OF THE INVENTION

Transdermal drug delivery offers many advantages over other types ofdrug delivery. With transdermal delivery, a localized delivery of drugmolecules can be achieved, which makes transdermal drug delivery targetspecific. Further, transdermal drug delivery avoids the gastrointestinal complications caused by oral delivery. While transdermal drugdelivery offers these and other advantages, a system than can quicklyand reliably deliver predictable quantities of drug molecules throughthe skin has heretofore not been developed.

The evolution of transdermal drug delivery has centered around patchtechnology. Patch technology is based on the ability to hold an activeingredient in constant contact with the epidermis. Over substantialperiods of time, drug molecules, held in such a state, will eventuallyfind their way into the bloodstream. Thus, patch technology relies onthe ability of the human body to pick up drug molecules through theskin. Transdermal drug delivery using patch technology has recently beenapplied for delivery of nicotine, in an effort to assist smokers inquitting, the delivery of nitroglycerine to angina sufferers, thedelivery of replacement hormones in post menopausal women, etc. Theseconventional drug delivery systems comprise a patch with an activeingredient such as a drug incorporated therein, the patch also includingan adhesive for attachment to the skin so as to place the activeingredient in close proximity to the skin.

Problems with patch technology abound. First, active drug molecules havea difficult time passing through the skin, as the skin poses asignificant barrier. In fact, in order for a drug molecule to reach thebloodstream, it must pass through the epidermis, stratum corneum (anespecially dense layer of cells), dermis and capillary cell structure.Second, real world conditions such as the patient's obesity, metabolismand circulatory efficiency can effectively prevent transdermal drugdelivery from occurring. Third, patch technology can be used only fortreatments involving extensively long treatment periods, since the flowrate of drug molecules is so small. Finally, patch adhesion to the skincauses extensive skin trauma as well as cosmetic problems. Specifically,most adhesives currently used tend to aggressively adhere to the skin sothat their removal may cause irritation and trauma. Indeed, subsequentpatches used by a given individual are often applied to a different areaof the skin in order to minimize such irritation and trauma.

In an effort to enhance the efficiency of transdermal drug delivery, theprior art teaches that by mixing certain individual ingredients(penetration enhancers) with a drug molecule, the ability of the drugmolecule to pass through the skin is increased somewhat. For example,U.S. Pat. No. 4,933,184 discloses the use of menthol as a penetrationenhancer; U.S. Pat. No. 5,229,130 discloses the use of vegetable oil(soybean and/or coconut oil) as a penetration enhancer; and U.S. Pat.No. 4,440,777 discloses the use of eucalyptol as a penetration enhancer.

Although mixing a penetration enhancer with a drug molecule helped tosomewhat increase the speed of drug delivery, problems were stillpresent. First, the aforementioned penetration enhancers constitute apassive, not an active, system. Thus, since they were not linked to thedrug molecule, the penetration of the enhancer does not necessarily meanthat the drug molecule has penetrated. In fact, the prior art drugmolecule penetration is only a by-product of the enhancer penetration.Second, even when drug molecule penetration has occurred, the prior artdoes not establish a condition whereby the blood supply to the transportarea is enhanced so as to maximize absorption speed. Third, prior artdoes not create a molecular structure that releases the drug moleculereadily within the acidic medium that constitutes blood, so as tomaximize bioavailability of the drug. Finally, although the prior arthas increased the speed of transport of the drug molecule transdermally,it is still not sufficiently fast so as to eliminate (if desired) theneed for a patch.

It is therefore an object of the present invention to provide atransdermal transport system that efficiently and easily allows foreffective delivery of an active ingredient through the skin and into theblood supply of an animal or human.

SUMMARY OF THE INVENTION

The problems of the prior art have been overcome by the presentinvention, which provides an efficient, predictable and reliable activeingredient transdermal delivery system that is sufficiently fast so asto eliminate (if desired) the need for a patch. More specifically, thepresent invention creates a molecular transdermal delivery vehicle thatcontains, as an integral part of the transdermal delivery molecule, theactive drug molecule. This molecularly uninhibited lacteal ensemble (or"MULE") is constructed of four elements, namely, a vasodilator, apenetration enhancer, the active ingredient, and a water soluble gum forlinking the vasodilator, penetration enhancer and active ingredient.

The advantages of the present invention over the prior art are many.First, the creation of a singular molecular unit that contains the drugmolecule and transdermally transports it constitutes the first activesystem. Unlike the prior art, any degree of molecular penetrationdirectly correlates to drug molecule penetration, hence it is alsopredictable. Second, the MULE enhances blood flow to thetransport/application site. Regardless of metabolism, obesity orcirculatory efficiency, the vasodilatory aspect of the MULE maximizesblood flow to the transport site so as to reliably maximize absorptionof the drug molecule. Third, the MULE is constructed in a manner thatwhen exposed to bodily fluids that are non-neutral in pH (i.e., havepH's that are less than or greater than 7.0), it breaks apart, therebyreleasing the drug molecule. This event insures bioavailability so thatdrug molecules are exposed to the blood supply and are capable of beingpicked up. Finally, the present invention operates on transport speedthat eliminates (if desired) the need for a patch.

DETAILED DESCRIPTION OF THE INVENTION

The invention comprises the creation of an molecular transdermaltransport vehicle that has at least four components, including theactive ingredient.

The first element of the MULE is one that enhances blood flow, throughvasodilatory action at the transport site. The vasodilator expands thesize of and blood supply to and from the local vascular network as wellas to the subdermal layer. Suitable ratios of vasodilators in the MULErange from about 1% to about 80% by weight, with ratios of from about 1%to about 33% being preferred. The amount of vasodilator will vary due toa number of factors, including the drug molecule size, drugconcentration, the desired delivery speed, the size of the surface areaof an application, and the application site. Excess amounts ofvasodilators can be used without impacting the performance of the MULE.Examples of non-irritational vasodilators include, by example only,bamethan sulphate, bencyclane fumarate, benpurodil hemisuccinate, benzylnicotinate, buflomedil hydrochloride, buphenine hydrochloride,butalamine hydrochloride, cetledil citrate, ciclonicate, cinepazidemaleate, cyclandelate, di-isopropylammonium dichloroacetate, ethylnicotinate, hepronicate, hexyl nicotinate, Ifenprodil tartrate, inositolnicotinate, isoxsuprine hydrochloride, kallidinogenase, methylnicotinate, maftidropuryl oxalate, nicametate citrate, niceritrol,nicobuxil, nicofuranose, nicotinyl alcohol, nicotinyl alcohol tartrate,nonidamide, oxpentifylline, papaveroline, pentifylline, pipratecol,propentofylline, raubasine, suloctidil, teasuprine, thymoxaminehydrochloride, xanthinol nicotinate, diazoxide, hydralazine, minoxidiland sodium nitropusside. Centrally acting agents include clonidine,quanaberz and methyl dopa. Alpha-adrenocaptor agents include indoramin,phenoxybenzamine, phentolamine and prazosin. Adrenergic neuron blockingagents include bethanidine, debrisoquine and guanethidine. ACEinhibitors include benazepril, captopril, cilazapril, enalapril,fosinopril, lisinopril, perindopril, quinapril and ramipril.Ganglion-blocking agents include pentolinium and trimetaphan.Calcium-channel blockers include amlodipine, diltiazem, felodipine,isradipine, nicardipine, nifedipine, nimodipine and verapamil.Prosteglandins include prostacyclin, thrombuxane A₂, leukotrienes, PGA,PGA₁, PGA₂, PGE₁, PGE₂, PGD, PGG and PGH. Angiotension II analogsinclude saralasin. Other vasodilators include nitroglycerin, labetalol,thrazide, isosorbide dinitrate, pentaerythritol tetranitrate, digitalis,hydralazine, diazoxide and sodium nitroprusside. One or morevasodilators can be used.

The second element of the MULE is an ingredient that functions as apermeation or penetration enhancer. Suitable enhancers include vegetableoil or a vegetable oil/alcohol mix. Suitable vegetable oils includepeanut oil, olive oil, sunflower oil, soybean oil, monoi oil andmacadamia oil, with olive oil being preferred. Suitable alcohols for thevegetable oil/alcohol mix include ethyl alcohol, isopropyl alcohol,methanol and witch hazel. Olive oil mixed with isopropyl alcohol is apreferred vegetable oil/alcohol mix. Eucalyptol is a further suitableexample of a vegetable oil/alcohol mix. Suitable ratios of vegetableoil:alcohol range from about 5:1 to about 1:10, preferably 1:2. Suitableamounts of vegetable oil or vegetable oil/alcohol mix in the MULE rangefrom about 1% to about 66% by weight, more preferably from about 10% toabout 33.3% by weight.

The third element of the MULE is the active ingredient. The term "activeingredient" is used herein to indicate any material or compositiondesired to be delivered transdermally, especially drugs. Examples ofactive ingredients that can be used in accordance with the presentinvention include acebutolol, acetaminophen, acetohydoxamic acid,acetophenazine, acyclovir, adrenocorticoids, allopurinol, alprazolam,aluminum hydroxide, amantadine, ambenonium, amiloride, aminobenzoatepotassium, amobarbital, amoxicillin, amphetamine, ampicillin, androgens,anesthetics, anticoagulants, anticonvulsants-dione type, antithyroidmedicine, appetite suppressants, aspirin, atenolol, atropine, azatadine,bacampicillin, baclofen, beclomethasone, belladonna,bendroflumethiazide, benzoyl peroxide, benzthiazide, benztropine,betamethasone, betha nechol, biperiden, bisacodyl, bromocriptine,bromodiphenhydramine, brompheniramine, buclizine, bumetanide, busulfan,butabarbital, butaperazine, caffeine, calcium carbonate, captopril,carbamazepine, carbenicillin, carbidopa & levodopa, carbinoxamineinhibitors, carbonic anhydsase, carisoprodol, carphenazine, cascara,cefaclor, cefadroxil, cephalexin, cephradine, chlophedianol, chloralhydrate, chlorambucil, chloramphenicol, chlordiazepoxide, chloroquine,chlorothiazide, chlorotrianisene, chlorpheniramine, chlorpromazine,chlorpropamide, chlorprothixene, chlorthalidone, chlorzoxazone,cholestyramine, cimetidine, cinoxacin, clemastine, clidinium,clindamycin, clofibrate, clomiphere, clonidine, clorazepate,cloxacillin, colochicine, coloestipol, conjugated estrogen,contraceptives, cortisone, cromolyn, cyclacillin, cyclandelate,cyclizine, cyclobenzaprine, cyclophosphamide, cyclothiazide, cycrimine,cyproheptadine, danazol, danthron, dantrolene, dapsone,dextroamphetamine, dexamethasone, dexchlorpheniramine, dextromethorphan,diazepan, dicloxacillin, dicyclomine, diethylstilbestrol, diflunisal,digitalis, diltiazen, dimenhydrinate, dimethindene, diphenhydramine,diphenidol, diphenoxylate & atrophive, diphenylopyraline, dipyradamole,disopyramide, disulfiram, divalporex, docusate calcium, docusatepotassium, docusate sodium, doxyloamine, dronabinol ephedrine,epinephrine, ergoloidmesylates, ergonovine, ergotamine, erythromycins,esterified estrogens, estradiol, estrogen, estrone, estropipute,etharynic acid, ethchlorvynol, ethinyl estradiol, ethopropazine,ethosaximide, ethotoin, fenoprofen, ferrous fumarate, ferrous gluconate,ferrous sulfate, flavoxate, flecainide, fluphenazine, fluprednisolone,flurazepam, folic acid, furosemide, gemfibrozil, glipizide, glyburide,glycopyrrolate, gold compounds, griseofuwin, guaifenesin, guanabenz,guanadrel, guanethidine, halazepam, haloperidol, hetacillin,hexobarbital, hydralazine, hydrochlorothiazide, hydrocortisone(cortisol), hydroflunethiazide, hydroxychloroquine, hydroxyzine,hyoscyamine, ibuprofen, indapamide, indomethacin, insulin, iofoquinol,iron-polysaccharide, isoetharine, isoniazid, isopropamide isoproterenol,isotretinoin, isoxsuprine, kaolin & pectin, ketoconazole, lactulose,levodopa, lincomycin liothyronine, liotrix, lithium, loperamide,lorazepam, magnesium hydroxide, magnesium sulfate, magnesiumtrisilicate,maprotiline, meclizine, meclofenamate, medroxyproyesterone, melenamicacid, melphalan, mephenytoin, mephobarbital, meprobamate,mercaptopurine, mesoridazine, metaproterenol, metaxalone,methamphetamine, methaqualone, metharbital, methenamine, methicillin,methocarbamol, methotrexate, methsuximide, methyclothinzide,methylcellulos, methyldopa, methylergonovine, methylphenidate,methylprednisolone, methysergide, metoclopramide, metolazone,metoprolol, metronidazole, minoxidil, mitotane, monamine oxidaseinhibitors, nadolol, nafcillin, nalidixic acid, naproxen, narcoticanalgesics, neomycin, neostigmine, niacin, nicotine, nifedipine,nitrates, nitrofurantoin, nomifensine, norethindrone, norethindroneacetate, norgestrel, nylidrin, nystatin, orphenadrine, oxacillin,oxazepam, oxprenolol, oxymetazoline, oxyphenbutazone, pancrelipase,pantothenic acid, papaverine, para-aminosalicylic acid, paramethasone,paregoric, pemoline, penicillamine, penicillin, penicillin-v,pentobarbital, perphenazine, phenacetin, phenazopyridine, pheniramine,phenobarbital, phenolphthalein, phenprocoumon, phensuximide,phenylbutazone, phenylephrine, phenylpropanolamine, phenyl toloxamine,phenytoin, pilocarpine, pindolol, piper acetazine, piroxicum, poloxamer,polycarbophil calcium, polythiazide, potassium supplements, pruzepam,prazosin, prednisolone, prednisone, primidone, probenecid, probucol,procainamide, procarbazine, prochlorperazine, procyclidine, promazine,promethazine, propantheline, propranolol, pseudoephedrine, psoralens,psyllium, pyridostigmine, pyrodoxine, pyrilamine, pyrvinium, quinestrol,quinethazone, quinidine, quinine, ranitidine, rauwolfia alkaloids,riboflavin, rifampin, ritodrine, salicylates, scopolamine, secobarbital,senna, sannosides a & b, simethicone, sodium bicarbonate, sodiumphosphate, sodium fluoride, spironolactone, sucrulfate, sulfacytine,sulfamethoxazole, sulfasalazine, sulfinpyrazone, sulfisoxazole,sulindac, talbutal, tamazepam, terbutaline, terfenadine, terphinhydrate,teracyclines, thiabendazole, thiamine, thioridazine, thiothixene,thyroblobulin, thyroid, thyroxine, ticarcillin, timolol, tocainide,tolazamide, tolbutamide, tolmetin trozodone, tretinoin, triamcinolone,trianterene, triazolam, trichlormethiazide, tricyclic antidepressants,tridhexethyl, trifluoperazine, triflupromazine, trihexyphenidyl,trimeprazine, trimethobenzamine, trimethoprim, tripclennamine,triprolidine, valproic acid, verapamil, vitamin A, vitamin B-12, vitaminC, vitamin D, vitamin E, vitamin K and xanthine. One or more activeingredients can be used. The active ingredient can be the same compoundas the vasodilator, where that compound exhibits both functions.

The final element that is essential to the creation of the MULE is theaddition of a water soluble gum. The water soluble gum binds the firstthree elements of the MULE together into the singular transport vehicle,and releases the active ingredient upon exposure to a fluid with anon-neutral pH. Suitable bodily fluids with a non-neutral pH includeblood, interstitial fluid, sweat, saliva, mucoid secretions, lymphaticfluid, oil, gastric juices, pericandial fluid, sinovial fluid,intercranial fluid, endolymph, perilymph, synaptic fluid, intersynapticfluid, and cerebrospinal fluid. Suitable water-soluble gums includeagar, arabic, carob, CMC, carrageenans, ghatti, guar, karaya, kadaya,locust bean, tragacanth and xanthan gums. The water soluble gum shouldbe used in an amount ranging from about 1% to about 33.3% by weight,most preferably an amount equal to the amount of active ingredient used.

The MULE is created by placing the penetration enhancer, thevasodilator, and the active ingredient in a mixing vessel, and agitatingthe combination over a sufficient period to achieve a uniform mix. Thewater soluble gum is then slowly added while continuing the agitation.After completion of the gum addition, agitation continues until mixuniformity is achieved. Other inactive ingredients may be added ifdesired.

Although the MULE transports drug molecules so efficiently that the needfor a patch is obviated, a patch can still be used where desired.Pre-packaged patches, pre-impregnated with the MULE can make presorbeddoses controllable. However, if a patch is used in conjunction with theMULE of the present invention, preferably the patch is a non-breathablelayer on which the active ingredient is placed. Suitable non-breathablelayers include sheets of plastic, polyethylene, polyvinyl chloride, waxpaper, foil, latex, etc., and combinations thereof. Those skilled in theart will recognize that any non-breathable substance (defined as asubstance that does not allow the exchange of gases through itsmembrane) that is not deleterious to the particular active ingredientbeing used and that does not cause any irritation upon contact with skincan be used.

The non-breathable layer functions to create and control a suitablemicroenvironment at the transport site. Too cold an environment canresult in little blood supply to the dermal barrier; pores and othernatural openings in the dermal barrier constrict, thereby preventingefficient transport. Too hot an environment can enhance secretion andperspiration and vapor flow through the dermal barrier, creatingnegative transport activity. Too dry an environment can cause an elementor elements of the MULE to evaporate quickly, losing its ability totransport. The enhanced evaporation also creates negative transportpressure. Too humid an environment can cause dilution of the activeingredient, diminishing the capacity of the active ingredient and alsocreating negative transport activity.

The non-breathable layer captures the body temperature and humidity,thereby maintaining temperature at the most efficient for transport, thepore size at or close to a maximum, and normal blood flow to the site.In addition, since body vapor is captured, a proper moisture level ismaintained. Preferably the temperature and humidity at the transportsite is about 85°-100° F. and 50-99%, respectively. The non-breathablelayer also creates a positive osmotic pressure back through the dermallayer, acting in a manner analogous to the so-called "greenhouseeffect". Vapor admitted through the skin passes through the MULE,collects along the non-breathable barrier and then passes back throughthe MULE and through the skin. Since the temperature is at about thebody temperature, the pore size is maximized and blood flow issufficient so that the active ingredient can be easily picked up by theblood through the dermal layer. If desired, the non-breathable layer canbe secured to the skin by any suitable means, such as with a bandagehaving adhesive or fasteners. In the preferred embodiment, no adhesiveis used, instead compression is used as discussed in detail below.

In order to further enhance blood supply to the transport site,compression can be utilized. Specifically, the non-breathable layer canbe applied to the skin tightly, such as with a tightly wrapped bandage.Preferably the compression at the transport site is greater than zeropounds per square inch but less than about 10 pounds per square inch.Too much compression can result in restricted blood supply. The positivepressure applied also aids in forcing the MULE through the dermal layerand into contact with the blood supply.

The non-breathable layer and wrapping material can be convenientlydesigned to accommodate specific transport sites. For example, thenon-breathable layer and wrap can be shaped in the form of a glove to beworn on one hand of the individual, or can be shaped in the form of aband to be worn on the arm or leg of the individual.

EXAMPLE 1

Vegetable oil, papaveroline and the active ingredient are placed in amixing vessel. The contents are then agitated therein to achieve auniform blend. Xanthan gum is then added slowly with the mixing vesselcontents being continually agitated. The agitation continues until auniform blend is achieved. Other inactive ingredients may be added, andagain the contents mixed until uniformity is achieved.

The contents are removed from the mixing vessel and are applied directlyto the skin at the desired transport site by gentle massaging forapproximately 60 seconds or until the mixture disappears.

What is claimed is:
 1. A transdermal delivery system for delivering anactive ingredient through the skin of a living body, comprising:a. anactive ingredient; b. a vasodilator; c. first means for enhancing thepermeation of said active ingredient through said skin; and d. secondmeans for binding said active ingredient and said vasodilator and firstmeans into a singular transport vehicle, said second means releasingsaid active ingredient upon contact with a bodily fluid having anon-neutral pH.
 2. The transdermal delivery system of claim 1, whereinsaid first means for enhancing the permeation comprises a vegetable oil.3. The transdermal delivery system of claim 1, wherein said first meansis selected from the group consisting of peanut oil, olive oil,sunflower oil, soybean oil, monoi oil, macadamia oil and a vegetableoil/alcohol mix.
 4. The transdermal delivery system of claim 1, whereinsaid second means comprises a water-soluble gum.
 5. The transdermaldelivery system of claim 2, wherein said second means comprises awater-soluble gum.
 6. The transdermal delivery system of claim 3,wherein said second means comprises a water-soluble gum.
 7. Thetransdermal delivery system of claim 4, wherein said water-soluble gumis selected from the group consisting of agar, arabic, carob, CMC,carrageenans, ghatti, guar, karaya, kadaya, locust bean, tragacanth andxanthan gum.
 8. The transdermal delivery system of claim 5, wherein saidwater-soluble gum is selected from the group consisting of agar, arabic,carob, CMC, carrageenans, ghatti, guar, karaya, kadaya, locust bean,tragacanth and xanthan gum.
 9. The transdermal delivery system of claim6, wherein said water-soluble gum is selected from the group consistingof agar, arabic, carob, CMC, carrageenans, ghatti, guar, karaya, kadaya,locust bean, tragacanth and xanthan gum.
 10. The transdermal deliverysystem of claim 1, further comprising means for controlling thetemperature and humidity at the site of transport of said activeingredient through said skin.
 11. The transdermal delivery system ofclaim 10, wherein said means for controlling the temperature andhumidity comprises a non-breathable layer.
 12. The transdermal deliverysystem of claim 1, wherein said non-neutral medium is selected from thegroup consisting of blood, interstitial fluid, sweat, saliva, mucoidsecretions, lymphatic fluid, sinovial fluid, endolymph, perilymph,synaptic fluid, intersynaptic fluid, and spinal fluid.
 13. A method ofdelivering an active ingredient through the skin of a living body,comprising:a. placing the active ingredient on the skin at a transportsite; b. enhancing the blood supply to the site of transport of saidactive ingredient through said skin by applying a vasodiloator to saidsite; c. enhancing the permeation of said active ingredient through saidskin by binding said active ingredient to a carrier with a water-solublegum; and d. allowing said active ingredient to be released from saidcarrier upon contact with a bodily fluid having a non-neutral pH. 14.The method of claim 13, further comprising controlling the temperatureand humidity at said transport site.
 15. The method of claim 14, whereinsaid temperature and humidity are controlled by covering said transportsite with a non-breathable material.
 16. The method of claim 13, whereinsaid non-neutral medium is selected from the group consisting of blood,interstitial fluid, sweat, saliva, mucoid secretions, lymphatic fluid,sinovial fluid, endolymph, perilymph, synaptic fluid, intersynapticfluid, and spinal fluid.